18-lower alkyl 20-keto-pregnanes

ABSTRACT

18-Lower alkyl androstenes are prepared by a sequence of steps from 3 Beta , 20 Beta -dihydroxypregn-5-en-18-oic acid 18,20lactone 3-acetate. The method proceeds through novel 18-lower alkyl pregnane intermediate compounds. These compounds are useful as intermediates and also possess antiestrogen activity. The 18lower androstene products possess various useful steroidal activities.

United States Patent 51 3,696,129 Edwards [451 Oct. 3, 1972 [54]IS-LOWER ALKYL ZO-KETO- [56] References Cited PREGNANES UNITED STATESPATENTS [72] Inventor: John A. Edwards, Los Altos, Calif.

3,381,003 4/1968 Patchett et a1 ..260/239.55 [73] Assgnee syme" Panama3,458,503 7/1969 Rees et al. ..260/239.55 Panama 3,465,009 9/1969 Telleret a]. ..260/397.4 [22] Filed: Oct. 9, 1970 I Primary Examiner-Henry A.French [21] Appl' 79706 Attorney-Evelyn K. Merker Related US.Application Data [63] Continuation-in-part of Ser. No. 538,581, [57]ABSTRACT March 30, 1966, Pat. No. 3,624,111, which is a 18-Lower alky]androstenes are prepared by a continuation-in-part of Ser. Nos. 528,398,Feb. sequence of steps from 313, ZOB-dihydroxypregn-S-en- 18, 1966, Pat.No. 3,402,173, and Ser. No. 18-oic acid 18,20-1actone 3-acetate. Themethod 441,297, March 19, 965, ab on proceeds through novel l8-1oweralkyl pregnane intermediate compounds. These compounds are useful as160/3973, 260/3974, 260/3975, intermediates and also possessantiestrogen activity. 260/999 The 18-1ower androstene products possessvarious [51] Int. Cl ..C07c 169/34 f l steroidal activities [58] Fieldof Search ../Machine Searched Steroids 11 Claims, No Drawings 18-LOWERALKYL ZO-KETO-PREGNANES This is a continuation-in-part of applicationSer. No. 538,581, filed Mar. 30, 1966, now U.S. Pat. No. 3,624,111,which is a continuation-in-part of applications Ser. No. 528,398, filedFeb. 18, 1966, now U.S. Pat. No. 3,402,173 and Ser. No. 441,297, filedMar. 19, 1965, now abandoned.

The present invention relates to novel and useful [8- lower alkylandrostene steroids, a method for preparing same, and novel andphysiologically useful intermediates also useful for preparing same.

The l8-lower alkyl androstenes of the present invention can berepresented by the following formula:

R2 CH2 wherein R represents 0x0 or the group H IR wherein R representshydrogen, hydroxy, or a carboxylic acyloxy group containing less than 12carbon atoms, preferably R is oxo, n representsa positive integer offrom I to 3, R represents hydroxy or a carboxylic acyloxy groupcontaining less than l2 carbon atoms, R represents hydrogen, lower alkylsuch as methyl, ethyl and the like, lower alkenyl suchas vinyl,prop-l-enyl, but-l-enyl, and the like, or lower alkynyl such as ethynyl,prop-Lynyl, and the like, and R and R taken together represents 0x0.

The carboxylic acyloxy groups of the compounds of the present inventioncontain less than 12 carbon atoms and may be of straight, branched,cyclic or cyclic-aliphatic chain structure. This structure may besaturated, unsaturated, or aromatic and optionally substituted byfunctional groups such as hydroxy, alkoxy containing up to five carbonatoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno,and the like. Typical esters thus include acetate, propionate,

enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,adamantoate, dichloroacetate, and the like.

The novel compounds of the present invention possess valuablephysiological properties. The compounds of the present invention whereinR is hydrogen or lower alkyl, for example methyl, ethyl or the like, arevaluable anabolic/androgenic compounds having a favorableanabolic/androgenic ratio. The compounds of the present inventionwherein R is a lower alkynyl such as ethynyl or a lower alkenyl such asvinyl demonstrate pituitary inhibition and progestational activity andare useful in the treatment of various menstrual disorders and in thecontrol and regulation of fertility. In addition, the novel compoundsare valuable anti-estrogenic agents. The compounds of the presentinvention wherein R is a lower alkenyl such as vinyllalso demonstratemarked anabolic activity. The compounds of the present invention may beadministered in the usual pharmaceutical compositions at dosagesappropriate for the condition being treated.

The compounds of the present invention are prepared according to aprocess which may be illustrated as follows.

C Hs-CHz-O In the above formulas, R represents a lower alkyl containingfrom one to three carbon atoms, i.e., methyl, ethyl or propyl, Rrepresents a carboxylic acyl group containing less than 12 carbon atoms,preferably acetoxy, and R represents lower alkyl such as methyl, ethyl,and the like, lower alkenyl such as vinyl, prop-lenyl, and the like, andlower alkynyl such as ethynyl, prop-l-ynyl, and the like.

In practicing the above illustrated process, the steroid startingmaterial I is reacted with a molar excess, preferably from about 10 molsto about 60 mols, more preferably about 10 to 40 mols, of a lower alkylmagnesium halide per mol of steroid starting material in suitablesolvent such as the aromatic hydrocarbons, for example, benzene,toluene, xylene, or the like, either alone or in admixture with lesseramounts of inert organic solvents such as dioxane, tetrahydrofuran, orthe like, at a temperature ranging from about 60 C. to about 150 C. andpreferably at the reflux temperature of the solvent employed for fromabout 24 hours to about 72 hours or longer depending upon temperatureand concentration of reactants, thus giving the 18- alkyl-l8-ketosteroid II. Suitable alkyl magnesium halides include the alkyl magnesiumbromides, chlorides, and iodides, preferably the chlorides, wherein saidalkyl contains from one to three carbon atoms, i.e. methyl, ethyl, andpropyl.

The l8-alkyl-l8-one steroid II is then treated with an excess ofhydrazine hydrate in an alcohol or glycol solvent such as ethanol,ethylene glycol, triethylene glycol, an the like, at an elevatedtemperature, preferably under reflux or about 145 C. or higher, for atime sufficient, generally about 5 hours or more, to obtain thecorresponding l8-alkyl-l8-hydrazone which upon treatment with a strongbase furnishes the corresponding IS-aIkyI-ZOB-hydroxy steroid III. Thetreatment with base is preferably accomplished by adding a solution ofthe l8-alkyl-l8-hydrazone in a solvent such as diethylene glycol to asolution of a strong base, e.g. sodium or potassium hydroxide, in anorganic solvent such as diethylene glycol while maintaining thetemperature of the base solution at about 215 to 240 C., preferably 225C.

The l8-alkyl-3B,2OB-diol steroid III is then subjected to ()ppcnaueroxidation to yield the steroid IV, l8-alkylprogesterone.

The l8-alkyl steroid IV is converted to the enol ether as by treatmentwith ethyl orthoformate to furnish the steroid V which upon treatmentwith an alkali metal tertiary alkoxide such as potassium t-butoxide inthe presence of oxygen gas affords the I7a-hydroperoxy steroid VI.

The l7a-hydroperoxy steroid VI is then converted into the3-keto-A-l7a-hydroxy steroid VII by treatment with, for example, zincdust in an acid medium such as acetic acid.

The l7a-hydroxy-l8-alkylprogesterone steroid VII is then converted into3B-hydroxy-l8-alkylandrost-4-enl7-one (VIII) by treatment with lithiumtri-t-butoxyaluminum hydride in tetrahydrofuran followed by reactionwith lead tetra-acetate.

The 3B-hydroxy-l7-one steroid VIII may be reduced as by treatment with,e.g. lithium tri-t-butoxyaluminum hydride in tetrahydrofuran, to furnishthe 313,17fl-diol steroid IX which upon oxidation by treatment with,e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in dioxane, furnishesthe corresponding 3-keto steroid X.

Alternatively, the 3B-hydroxy-l7-keto steroid VIII may be transformedinto the 3B,l7B-diol steroid XI having a 17a-substituent such as alkyl,alkenyl or alkynyl. The l7a-alkynyl derivatives of the steroid XI (XI, Ralkynyl) may be obtained by treating the l7-keto steroid VIII with, e.g.potassium acetylide, potassium methylacetylide, and the like, in liquidammonia. By treatment of the l7-keto steroid VIII with analkenylmagnesium halide, e.g. vinylmagnesium bromide, lpropenylmagnesiumbromide, and the like, the corresponding 313,17B-diol-l7a-alkenylsteroid is obtained (XI, R alkenyl). Similarly, by treatment of the l7-keto steroid VIII with, e.g. an alkylmagnesium bromide such asmethylmagnesium bromide in ether, there are obtained the corresponding3,13,17B-diol-17a-alkyl compounds(XI, R =alkyl).

The 3B,l7B-diol steroid XI may be transformed into the corresponding3-keto steroid XII by treatment with, e. g. 2,3-dichloro-5 ,6-dicyano-l,4-benzoquinone in tetrahydrofuran, dioxane, and the like.

The thus-obtained 3-keto steroids (X and XII) may be transformed intothe corresponding 3-desoxy derivatives by thioketalization followed bydesulfurization with Raney nickel or sodium in liquid ammonia.

The compounds of the present invention containing a free hydroxyl may beesterified and etherified in the conventional manner. Thus, the freehydroxyl containing compounds may be esterified as through the use ofcarboxylic acid anhydride and p-toluenesulfonic acid in acid oretherified through the use of dihydropyran or dihydrofuran and an acidcatalyst.

The l8-lower alkyl pregnenes represented above by Formulas (IV) and(VII) and the l7a-carboxylic esters thereof, are novel. These compoundscan be further represented by the following Formula (A):

of the present invention, as described hereinbefore. The compounds ofFormula (A) are also physiologically useful, possessing unexpectedlyimproved anti-estrogen activity. Thus, in standard tests conducted foranti-estrogenic activity in accordance with the procedure of Dorfman etal., Endocrinology 68, 17 et seq. (1961) and Emmens, Methods in HormoneResearch, Academic Press, Vol. 2, page 3; New York City, (1962); it wasdemonstrated that l8-methylprogesterone has three times the subcutaneousanti-estrogen activity of progesterone.

The following examples further illustrate the present invention.

EXAMPLE 1 A mixture of 28 g. of 3B,20B-dihydroxypregn-5-enl8-oic acid18,20-lactone-3-acetate and 700 ml. of toluene is heated under refluxwith 3N-methyl magnesium chloride in tetrahydrofuran (400 ml.) for 4days. The reaction mixture is cooled, poured onto ice, diluted withwater and extracted with ethyl acetate. The organic layer is washed withwater, dried and evaporated to yield3B,2OB-dihydroxy-l8-methylpregn-S-en-lS-one which may be crystallizedfrom acetonezhexane.

A solution of 12.2 g. of 3,8,20,8-dihydroxy-l8- methylpregn-5-en-l8-onein 400 ml. of triethylene glycol is heated under reflux at 145 C. with80 ml. of 80 percent hydrazine hydrate and 25 g. of hydrazinedihydrochloride for 5 hours. The mixture is then allowed to cool andthereafter poured into water. The mixture is then extracted with ethylacetate and the organic layer washed with water, dried and evaporated todryness to yield the corresponding l8-hydrazone derivative which may becrystallized from ethyl acetatezhexane.

A solution of 20 ml. of 100 percent hydrazine hydrate in 200 ml. ofdiethylene glycol is distilled, under nitrogen, until the internaltemperature reaches 225 C. Ten grams of potassium hydroxide is thenadded cautiously and distillation continued, under nitrogen, until thetemperature again reached 225 C. A solution of 15 of the abovel8-hydrazone derivative in 150 ml. of diethylene glycol is then addedslowly while maintaining the temperature of the reaction at reflux at225 C. The resulting solution is then heated under reflux in a nitrogenatmosphere for 5 hr., cooled, diluted with water and the precipitatewhich forms collected by filtration, washed with water and dried undervacuum to yield l8-methylpregn-5-ene-3B,2OB-diol which may becrystallized from methanol.

A solution of 2.2 g. of 18-methylpregn-5-ene-3 ,B,20B-diol in 50 ml. oftoluene and 8 ml, of cycl0hexanone is boiled until ml. of distillate iscollected. Three milliliters of cyclohexanone and 2 g. of aluminumisopropoxide are then added and the mixture heated at reflux for min.,cooled, and poured into 150 ml. of water containing 5 ml. of aceticacid. The mixture is steam-distilled to remove solvents and theresulting emulsion extracted 3 times with 150 ml. portions of ether. Theorganic layer is washed with water, ZN-hydrochloric acid and saturatedsodium bicarbonate solution, dried and evaporated. The residue isdissolved in hexane: benzene (2:1) and absorbed on alumina. Elution withbenzene yields l8-methylprogesterone.

A mixture of 1 g. of l8-methylprogesterone, 10 ml. of dioxane, 1 ml. ofethyl orthoformate, and 50 mg. of p-toluene-solfonic acid in thepresence of Drierite, at 25 C., is stirred for 2.5 hours. The mixture isthen poured into aqueous potassium bicarbonate and extracted with ether.The ether extract is dried over sodium sulfate and evaporated in thepresence of a trace of pyridine. The resulting residue is dissolved inhex anezbenzene (4:1) and filtered through alumina furnishing 3-ethoxyl8-methylpregna-3 ,5-dien-20-one which may be crystallized from methanolcontaining a trace of pyridine,

A solution of 500 mg of the above enol-ether in 5 ml. of tetrahydrofuranis added to 15 ml. of 1N-potassium t-butoxide in t-butanol and theresulting solution shaken at 0 C. under an atmosphere of oxygen. Theuptake of oxygen ceases at 35 ml. after 15 minutes. The solution is thenneutralized to pH-7 by lN-acetic acid,

extracted with ethyl acetate and the organic layer 1 washed with water,dried and evaporated to dryness at 30 C. The residue is crystallizedfrom acetone: water to yield 17a-hydroperoxy-3-ethoxy-l 8-methylpregna-3,5-dien-20-one.

A mixture of 3.1 g. of the above l7oz-hydroperoxy compound in ml. ofacetic acid is stirred with 6 g. of zinc dust at 25 C. for 12 hours. Themixture is then filtered and the residue washed with ether. The filtrateis diluted with ether and the organic layer washed with water and sodiumbicarbonate solution, dried and evaporated to dryness. Purification ofthe residue by means of preparative thin layer chromatography on HF.silica gel chloroform: methanol (9: 1) affords17ahydroxy-lS-methylprogesterone which may be crystallized fromacetonezhexane.

A solution of 4.0 g. of 17a-hydroxy-l8-methylprogesterone in 200 ml. ofdry tetrahydrofuran is stirred with 20 g. of lithiumtri-t-butoxyaluminum hydride at 0 C. for 7 hours and the mixtureconcentrated to a small volume under vacuum. The residue is extractedwith ethyl acetate and the organic layer washed with water and saturatedsodium bicarbonate solution, dried and evaporated to dryness. Thisproduct in 200 ml. of acetic acid is reacted with 12 g. of leadtetra-acetate at 25 C. with stirring for 1.3 hours. About 20 ml. ofethylene glycol is then added to destroy the excess of oxidant and theresulting solution diluted with water and extracted with ethyl acetate.The organic layer is then washed with water and saturated sodiumbicarbonate solution dried and evaporated to dryness. The resultingresidue is dissolved in hexanezbenzene (1:1), adsorbed on alumina andeluted with benzenerether (19:1) to yield 3B-hydroxy-l8-methylandrost-4-en-l7-one which may be crystallized fromacetone2hexane.

Similarly, by repeating the process of this example using ethylmagnesiumchloride or n-propylmagnesium chloride in lieu of methylmagnesiumchloride, there is obtained SB-hydroxy- 1 8-ethylandrost-4enl 7-one and3/3-hydroxy- 1 8-n-propylandrost-4-en-l 7-one, respectively. At the sametime, l8-ethylprogesterone, 17ahydroxy-18-ethylprogesterone, l8-n-propylprogesterone, and 1 7a-hydroxyl 8-n-propylprogesterone areprepared.

The l 7a-hydroxyl 8-methylprogesterone compound prepared in accordancewith the foregoing procedure can be conventionally esterified to preparethe corresponding C-l7a carboxylic acyloxy esters thereof, such as theacetate, propionate, butyrate, and so forth-see the paragraph common topages 7 and 8. For example,

A mixture of l g. of l7a-hydroxy-l8-methylprogesterone l g. ofp-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and 25 ml. ofacetic anhydride is allowed to stand at room temperature for 24 hours,and then is poured into water and stirred. This mixture is thenextracted with methylene chloride and these extracts are dried andevaporated. The residue is then dissolved in 250 ml. of methanolcontaining ml. of concentrated hydrochloric acid. After refluxing for 1hour, the mixture is neutralized with an aqueous percent solution ofpotassium bicarbonate and evaporated. The residue is extracted withmethylene chloride, and the methylene chloride extract is washed withwater to neutrality, dried and evaporated to yield 1 7a-acetoxyl8-methylprogesterone which is recrystallized from acetonezether.

Similarly, l7a-acetoxyl 8-ethylprogesterone andl7a-acetoxy-l8-n-propylprogesterone are prepared as well as the otherC-l7a carboxylic acyloxy esters thereof, e.g., propionates, butyrates,valerates, etc.

EXAMPLE 2 A mixture of l g. of 3B-hydroxy-l8-methylandrost-4- en-l7-onein ml. of dioxane, and 1.1 molar equivalents of2,3-dichloro-5,6-dicyano-l ,4- benzoquinone is allowed to stand at roomtemperature for 3 hours. The solid formed during the reaction is removedby filtration and the filtrate evaporated to dryness. The residue isdissolved in acetone and filtered through 20 g. of alumina to yieldl8-methylandrost-4- ene-3,l7-dione which may be further purified byrecrystallization from acetone:hexane.

Similarly, using 3B-hydroxy-l8-ethylandrost-4-enl 7-one and 3/3-hydroxyl8-n-propylandrost-4-enl 7- one as the starting material in the foregoingprocedure, there are obtained the corresponding 3,17-dione compounds.

EXAMPLE 3 A mixture of 250 mg. of3B-hydroxy-l8-methylandrost-4-en-l7-one, 650 mg. of lithiumt-butoxyaluminum hydride and 13 ml. of tetrahydrofuran is stirred at C.for 2 hours. The reaction mixture is then extracted with ether and thecombined ether extracts are washed with water, dried and evaporated todryness to yield l8-methylandrost-4-ene, 3B,l7B-diol which may becrystallized from acetone:hexane.

In a similar manner, 3B-hydroxy-l8-ethylandrost-4- en- 1 7-one and3B-hydroxy-l 8-n-propylandrost-4-enl7 -one may be converted into thecorresponding 3,8,17B-diol compound.

EXAMPLE 4 A mixture of 170 mg. of l8-methylandrost-4-ene-3 [3,17,8-diol,200 mg. of 2,3-dichloro-5,6-dicyano-l,4- benzoquinone and 5 ml. ofanhydrous dioxane is allowed to stand at 25 C. for 2.5 hours and then at0 C. for IS hours. The reaction mixture is then diluted with 40 ml. ofdichloromethane and adsorbed on 50 g. of alumina. Elution with etheraffords 17B-hydroxy-l8- methylandrost-4-en-3-one which is purified bypreparative thin layer chromatography, on HF silica gel, inchloroformzmethanol (30:1) and may be crystallized from acetone:hexaneas needles.

Likewise, through the use of the above procedure, the l7B-hydroxy-3-ketoderivatives of l8-ethylandrost- 4-ene-3B, l 7B-diol andl8-n-propylandrost-4-ene-3 B, 17,8-diol are obtained.

EXAMPLE 5 A solution of 980 mg. of3/3-hydroxy-l8-methylandrost-4-en-l7-one in 5 ml. of dichloromethane and20 ml. of ether is added to a solution of potassium acetylide (from 390mg. potassium metal) in ml. of liquid ammonia. The resulting mixture isstirred for 6 hours. Then 800 mg. of ammonium chloride is added and theammonia allowed to evaporated overnight. The residue is extracted withdichloromethane and water and the organic layer is washed with water,dried over sodium sulfate and evaporated to give a substantiallypale-yellow solid. This crude product is adsorbed on 100 g. of aluminaand elution with benzene:ether (4:1 and 1:1) affords a mixture ofl7a-ethynyl-l8-methylandrost-4-ene-3B,17B-diol and the unchanged 3B-hydroxy-l8-methylandrost-4-en-l7-one from which thel7a-ethynyl-3B,l7fi-diol compound is isolated by crystallization fromacetone:hexane.

In a similar manner, 3B-hydroxy-l8-ethylandrost-4- en- 1 7-one and3B-hydroxy-l 8-n-propylandrost-4-enl7-0ne are converted into thecorresponding l7a-ethynyl-3B, l 7B-diol compounds.

Likewise, through the use of other acetylides, e.g. potassiummethylacetylide, the corresponding l7a-alkynyl derivatives may beobtained.

EXAMPLE 6 A solution of 5 g. of 3B-hydroxy-l8-methylandrost- 4-en-l7-onein 250 ml. of thiophene-free benzene is treated with 10 molarequivalents of vinylmagnesium bromide in anhydrous ether. The mixture isheated at reflux under anhydrous conditions for 24 hours, cooled, andcautiously treated with excess aqueous ammonium chloride solution. Theresulting mixture is then extracted with ethyl acetate, the extractswashed with water, dried over sodium sulfate, and evaporated to drynessfurnishing l7a-vinyl-l8-methylandrost-4- ene-3B,l7B-diol which may bepurified by crystallization from methylene chloridezhexane.

By repeating the foregoing procedure using other alkenylmagnesiumbromides, e.g. isopropenylmagnesium bromide, l-propenylmagnesiumbromide, and the like, in lieu of vinylmagnesium bromide, thecorresponding l7a-alkenyl derivatives are obtained.

Similarly by using 3B-hydroxy-l 8-ethylandrost-4-enl7-one or 3B-hydroxyl8-n-propylandrost-4-enl 7-one in place of3B-hydroxy-l8-methylandrost-4-en-l7-one, the correspondingl7a-alkenyl-3/3,l7/3-diol compounds are obtained.

EXAMPLE 7 To a stirred solution of 2 g. of 3,8-hydroxy-l8-methyl-androst-4-en-l7-one in 250 ml. of absolute ether is added in adropwise fashion and under nitrogen, an ethereal solution of molarequivalents of ethyl lithium. The mixture is then stirred for 48 hoursat room temperature, poured into water, acidified with hydrochloric acidand stirred vigorously for 1 hour. The ethereal phase is separated,washed with water to neutrality, dried over sodium sulfate, andevaporated to dryness to yieldl7a-ethyl-l8-methylandrost-4-ene-3B,l7/3-diol which may be furtherpurified through recrystallization from acetonezhexane.

EXAMPLE 8 A solution of 5 g. of ZB-hydroxy-l8-methylandrost- 4-en-l7-onein 250 ml. of thiophene-free benzene is treated with an equimolar amountof methylmagnesium bromide in anhydrous ether. The mixture is heated atreflux under anhydrous conditions for 3 hours, cooled, and cautiouslytreated with excess aqueousammonium chloride solution. This mixture isthen extracted with ethyl acetate and these extracts are in turn washedwith water, dried over sodium sulfate and evaporated to dryness to yieldl7a,l8-dimethylandrost-4-ene-3B,17/3- diol which may be recrystallizedfrom methylene chloridezhexane.

EXAMPLE 9 A mixture of 1 g. of l7a-ethynyl-lS-methylandrost-4-ene-3B,17B diol in ml. of dioxane and 1.1 molar equivalents of2,3-dichloro-5,6-dicyano-1,4- benzoquinone is stirred at C. for 5.5hours. The reaction mixture is then filtered and the filtrate evaporatedto dryness. The residue is dissolved in methylene chloride and filteredthrough 20 g. of alumina to yieldl7a-ethynyl-17/3-hydroxy-l8-methylandrost-4-en-3-one which may bepurified by recrystallization from acetone:hexane.

By repeating the process of this example using as the starting material,the other 3B,l7B-diol compounds of the present invention, e.g.17a-ethynyl-18-ethylandrost-4-ene-3B, 17B-diol, l 7a-vinyl- 18-methylandrost- 4-ene-3,B,17B-diol, 17a, 1 8'-dimethylandrost-4-ene-3,B,1 7B-diol, the corresponding l7B-hydroxy-3-one compounds areobtained, e.g. 17a-ethynyl-17B- hydroxyl 8-ethylandrost-4 -eri-3-one, l7avinyl- 1 7B- hydroxy -l 8-methylandrost-4-en-3-one and 1 7B- hydroxy-1 7a, 1 8-dimethylandrost-4-en-3-one.

EXAMPLE 10 A solution of 5 g. of 17a-ethynyl-l7B-hydroxy-l8-methylandrost-4-en-3-one in 100 ml. of glacial acetic acid containing 5ml. of ethane dithiol and 4 ml. of a saturated solution of hydrogenchloride in acetic acid, is allowed to stand at room temperature for 4hours. Water is added and the resulting mixture then extracted withethyl acetate. The extracts are washed with a 5 percent aqueous sodiumbicarbonate solution and water, dried over sodium sulfate and evaporatedto dryness. The residue is recrystallized from ether:hexane and 4 g. ofthis material in 3 liters of ethanol (previously distilled over Raneynickel) is heated at reflux with 50 g. of degassed Raney nickel for 6hours. The metal is removed by filtration and washed with hot ethanoland the filtrate evaporated to dryness, The residue is dissolved inchloroform and this chloroform EXAMPLE 1 1 Two milliters of dihydropyranare added to a solution of 1 g. of17a-ethynyl-l7B-hydroxy-l8-methylandrost- 4-en-3-one in 15 ml. ofbenzene. About I ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield l7a-ethynyl-l7B-(tetrahydropyran-2'-y1oxy)- l8-methylandrost- 4-en-3-one which is recrystallized from pentane.

By repeating the process of this example using the otherl7B-hydroxy-3-one and 17B-hydroxy-3-desoxy compounds of the presentinvention, the corresponding l7B-tetrahydropyranyl ethers are obtained.

Likewise, by repeating the above process with the exception of usingdihydrofuran in lieu of dihydropyran, the correspondingl7B-tetrahydrofuranyl ethers are obtained, e. g. l 7a-ethynyl-17B-(tetrahydrofuran-2- yloxy)-l 8-methylandrost-4-en-3-one.

EXAMPLE 12 A mixture of l g. of 17a-ethynyl-17B-hydroxy-l8-methyl-androst-4-en-3-one, 1 g. of p-toluenesulfonic acid monohydrate,50 ml. of acetic acid and 25 ml. of acetic anhydride is allowed to standat room temperature for 24 hours and is then poured into water andstirred. This mixture is then extracted with methylene chloride andthese extracts are dried and evaporated to yield l7a-ethynyll7B-acetoxyl 8-methylandrost-4- en-3-one.

By repeating the process of this example, using the other17B-hydroxy-3-one and l7fl-hydroxy-3-desoxy compounds of the presentinvention, the corresponding l7B-acetoxy compounds are obtained.

Similarly, through the use of other carboxylic acid anhydrides in theprocess of this example, other 175- acylates may be obtained.

EXAMPLE 13 One gram of lithium tri-t-butoxyaluminum hydride is added toan ice cooled solution of l g. ofl7a-ethynyll7B-acetoxy-l8-methylandrost-4-en-3-one in ml. of drytetrahydrofuran and the mixture is then allowed to stand for 16 hours atroom temperature. The excess reagent is decomposed by addition of waterand the solution is then concentrated to small volume in vacuo anddiluted with water. The product is extracted with ethyl acetate andthese extracts are washed with water, dried and evaporated to yieldl7a-ethynyl-l7B-acetoxyl 8-methylandrost-4-en-3B-ol which may be furtherpurified by recrystallization from acetone:hexane.

Similarly, the process of this example may be used to convert other3-keto compounds of the present invention into the corresponding3,8-hydroxy derivative, e.g. l7a-vinyll 7B-acetoxy-l8-methylandrost-4-en-3B-ol, l7a-ethynyl-l 7B-(tetrahydropyran-2'-yloxy l8- methylandrost-4-en-3,8-0], etc.

EXAMPLE l4 A mixture of l g. of l7a-ethynyl-l7B-hydroxy-l8-methylandrost-4-en-3-one, l g. of p-toluenesulfonic acid monohydrate, 50ml. of dichloroacetic acid, and 25 ml. of dichloroacetic acid anhydrideis allowed to stand at room temperature for 24 hours, and then pouredinto water and stirred. This mixture is then extracted with methylenechloride and the organic extracts are dried and evaporated to yield 173-dichloroacetoxyl 7a-ethynyl-l 8-methylandrost-4-en- 3-one.

By repeating the process of this example, using as the starting materialthe other l7B-hydroxy-3-one and l7B-hydroxy-3-desoxy compounds of thepresent invention, there are obtained the corresponding 17,8-dichloroacetoxy derivatives.

mixture ul 2 g. of l lli-hytllnxy-l lmethynyl-Hlmethylandrost-4-en-3-onein 8 ml. of pyridine and 4 ml. of adamantoyl chloride is heated at steambath temperatures for 1 hour. The mixture is then poured into ice waterand the solid which forms is collected by filtration, washed with waterand dried to yield l7B-adamantoyloxyl 7a-ethynyll8-methylandrost-4-en-3-one which is further purified throughrecrystallization from methylene chloridezhexane.

EXAMPLE 16 A mixture of l g. of l7a-ethynyl-l7B-hydroxy-l8-methyl-androst-4-en-3-one, l g. of p-toluenesulfonic acid monohydrate,50 ml. of propionic acid and 25 ml. of propionic acid anhydride, isallowed to stand at room temperature for 24 hours and is then pouredinto water and stirred. This mixture is then extracted with methylenechloride and these extracts are dried and evaporated to yieldl7a-ethynyl-l7/3-hydroxy-l8- methylandrost-4-en-3-onel 7-propionate.

Likewise, through the use of the other l7fi-hydroxy- 3-one andl7B-hydr0Xy-3-desoxy compounds of the present invention in the processof this example, the corresponding l7,B-propionate is obtained.

EXAMPLE 17 A mixture of l g. of l7a-ethynyl-l8-methylandrost-4-en-3B,l7,B-diol, 4 ml. of pyridine and 2 ml. of acetic anhydride isallowed to stand at room temperature for hours. The mixture is thenpoured into ice water and the solid which forms is collected byfiltration, washed with water and dried to yield3B-acetoxy-l7a-ethynyll8-methylandrost-4-en-l7B-ol which may be furtherpurified through recrystallization from acetonezhexane.

By repeating the process of this example using other 3,8-hydroxycompounds of the present invention as the starting material, thecorresponding 3B-acetoxy compounds are obtained.

EXAMPLE 18 A mixture of 1 g. of l7a-ethynyl-18-methylandrost-4-ene-3B,l7B-diol, l g. of p-toluenesulfonic acid monohydrate, 50 ml. ofacetic acid and 25 ml. of acetic anhydride is allowed to stand at roomtemperature for 24 hours and then poured into water and stirred. Thismixture is then extracted with methylene chloride and these extracts aredried and evaporated to yield 313,173 -diacetoxyl 7a-ethynyl-l8-methylandrost-4-ene which is recrystallized from acetonezether.

Similarly, the other 3B,l7B-diol compounds of the present invention aretransformed into the corresponding 33,1 7,8-diacetoxy compounds.

EXAMPLE 19 Five milliliters of dihydropyran are added to a solution of lg. of l7a-ethynyl-l8-methylandrost-4-ene- 3B,17B-diol in 20 ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.6 g. of p-toluenesulfonic acid is added to the cooled solution. Thismixture is allowed to stand at room temperature for 4 days, and is thenwashed with aqueous sodium bicarbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 38,17B- his (tetrahydropyran-2-yloxy)- l7a-ethyny|- l 8-methylztmlnml 4 our Similarly, using dihytlml'urun inplace dihydropyran in the foregoing procedure, there is obtained thecorresponding 3B,l7B-bis tetrahydrofuranyl ether.

EXAMPLE 20 Two milliliters of dihydropyran are added to a solution of lg. of l7a-ethynyl-l7B-acetoxy-l8-methylandrost-4-en-3B-ol in 15 ml. ofbenzene. About 1 ml. is removed by distillation to remove moisture and0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution.This mixture is allowed to stand at room temperature for 4 days, and isthen washed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 3,8- (tetrahydropyran-2-yloxy 1 7a-ethynyll7B-acetoxyl8-methylandrost-4-ene which is recrystallized from pentane.

The corresponding tetrahydrofuranyl ether is obtained by usingdihydrofuran in place of dihydropyran in the above process.

What is claimed is:

l. A compound selected from those represented by the formula:

8. The compound according to claim I which is 18-11- propylprogesterone.

9. The compound according to claim 1 which is l7ahydroxyl8-n-propylprogesterone.

10. The compound according to claim 1 which is l 7a-acetoxyl8-n-propylprogesterone.

11. The compound according to claim 1 which is a carboxylic acyloxy ofless than 12 carbon atoms ester of a l7a-hydroxyl 8-lower alkylprogesterone.

2. The compound according to claim 1 which is 18-methylprogesterone. 3.The compound according to claim 1 which is 17 Alpha-hydroxy-18-methylprogesterone.
 4. The compound according to claim 1which is 17 Alpha -acetoxy-18-methylprogesterone.
 5. The compoundaccording to claim 1 which is 18-ethylprogesterone.
 6. The compoundaccording to claim 1 which is 17 Alpha -hydroxy-18-ethylprogesterone. 7.The compound according to claim 1 which is 17 Alpha-acetoxy-18-ethylprogesterone.
 8. The compound according to claim 1which is 18-n-propylprogesterone.
 9. The compound according to claim 1which is 17 Alpha -hydroxy-18-n-propylprogesterone.
 10. The compoundaccording to claim 1 which is 17 Alpha -acetoxy-18-n-propylprogesterone.11. The compound according to claim 1 which is a carboxylic acyloxy ofless than 12 carbon atoms ester of a 17 Alpha -hydroxy-18-lower alkylprogesterone.